rs112927502

Variant names:

• chr2-166204478-C-A
• rs112927502
• NM_001365536.1:c.4399-14G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-166204478-C-A
• chr2-166204478-C-G
• chr2-166204478-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001365536.1(SCN9A):​c.4399-14G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000824 in 611,678 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00067 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00086 (5 hom.)
• Consequence: SCN9A NM_001365536.1 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.08
• Publications: 2 publications found

Genes affected

SCN9A (HGNC:10597): (sodium voltage-gated channel alpha subunit 9) This gene encodes a voltage-gated sodium channel which plays a significant role in nociception signaling. Mutations in this gene have been associated with primary erythermalgia, channelopathy-associated insensitivity to pain, and paroxysmal extreme pain disorder. [provided by RefSeq, Aug 2009]

SCN1A-AS1 (HGNC:54069): (SCN1A and SCN9A antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 2-166204478-C-A is Benign according to our data. Variant chr2-166204478-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258886.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000671 (80/119206) while in subpopulation EAS AF = 0.0156 (61/3916). AF 95% confidence interval is 0.0124. There are 0 homozygotes in GnomAd4. There are 51 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 AD,SD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.4399-14G>T		intron_variant	Intron 24 of 26	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.4399-14G>T		intron_variant	Intron 24 of 26		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.4399-14G>T		intron_variant	Intron 24 of 26	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.4366-14G>T		intron_variant	Intron 24 of 26	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.4366-14G>T		intron_variant	Intron 24 of 26			ENSP00000495983.1

Frequencies

GnomAD3 genomes AF: 0.000663 AC: 79 AN: 119100 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0158

Gnomad SAS AF: 0.00364

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000540

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00118 AC: 226 AN: 191076 AF XY: 0.00118

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0166

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000433

Gnomad OTH exome AF: 0.000235

GnomAD4 exome AF: 0.000861 AC: 424 AN: 492472 Hom.: 5 Cov.: 13 AF XY: 0.000879 AC XY: 226 AN XY: 257032

African (AFR) AF: 0.00 AC: 0 AN: 11358

American (AMR) AF: 0.000146 AC: 3 AN: 20604

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11828

East Asian (EAS) AF: 0.0138 AC: 314 AN: 22706

South Asian (SAS) AF: 0.00165 AC: 68 AN: 41100

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29334

Middle Eastern (MID) AF: 0.00110 AC: 2 AN: 1816

European-Non Finnish (NFE) AF: 0.0000121 AC: 4 AN: 329440

Other (OTH) AF: 0.00136 AC: 33 AN: 24286

GnomAD4 genome AF: 0.000671 AC: 80 AN: 119206 Hom.: 0 Cov.: 31 AF XY: 0.000883 AC XY: 51 AN XY: 57732

African (AFR) AF: 0.00 AC: 0 AN: 31342

American (AMR) AF: 0.00 AC: 0 AN: 11750

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2780

East Asian (EAS) AF: 0.0156 AC: 61 AN: 3916

South Asian (SAS) AF: 0.00416 AC: 16 AN: 3846

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 212

European-Non Finnish (NFE) AF: 0.0000540 AC: 3 AN: 55578

Other (OTH) AF: 0.00 AC: 0 AN: 1596

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary erythromelalgia Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Channelopathy-associated congenital insensitivity to pain, autosomal recessive Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Generalized epilepsy with febrile seizures plus, type 7;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A Benign:1

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Small fiber neuropathy Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Paroxysmal extreme pain disorder Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.28
DANN	Benign	0.49
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs112927502; hg19: chr2-167060988; COSMIC: COSV57617017;